Phase 1 study of the novel enhancer of zeste homolog 2 (EZH2) inhibitor GSK2816126 in patients with advanced hematological and solid tumors

Purpose: To test inhibition of enhancer of zeste homolog 2 (EZH2) activity for cancer therapy. Experimental Design: This phase 1 study determined the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of the intravenously administered, highly selective EZH2 inhibitor, GSK2816126, (NCT02082977).Doses of GSK2816126 ranged from 50-3000 mg twice weekly, and GSK2816126 was given 3-weeks-on/1-week-off in 28-day cycles. Eligible patients had solid tumors or B-cell lymphomas with no available standard treatment regimen. Results: Forty-one patients (21 solid tumors, 20 lymphoma)received treatment. All patients experienced ≥1 adverse event (AE). Fatigue (22/41 [53.7%]) and nausea (20/41 [48.8%]) were the most common toxicity. Twelve(32%) patients experienced a serious AE. Dose-limiting elevated liver transaminases occurred in two of 7 patients receiving 3000 mgof GSK2816126; 2400 mg was therefore established as the MTD. Following intravenous administration of 50-3000 mg twice weekly, plasma GSK2816126 levels decreased biexponentially, with a mean terminal elimination half-life of approximately 27 hours. GSK2816126 exposure (maximum observed plasma concentration and area under the plasma-time curve) increased in a dose-proportional manner. No change from baseline in H3K27me3 was seen in peripheral blood mononuclear cells. Fourteen of 41 (34%) patients had radiological best response of stable disease, 1 patient with lymphoma achieved a partial response, 21 of 41 (51%) patients had progressive disease and 5 were unevaluable for antitumor response. Conclusions: The MTD of GSK2816126 was established at 2400 mg, but the dosing method and relatively short half-life limited effective exposure, and modest anticancer activity was observed at tolerable doses.